Inhaled asbestos and crystalline silica are recognized as occupational and ubiquitious fibrognic particles, both capable of inducing lung inflammation and fibrosis. Despite well-established recognition of fibrogenesis from these particles at an anatomic level, the molecular and cellular mechanisms of fibrosis remain poorly understood. The proposed research postulates three main hypotheses: 1) silica and asbestos mediate alveolar macrophage (AM) apoptosis through the scavenger receptor class A (SRA) and this process requires participation of one or more caspases; 2) stimulatory AM phenotype are the most resistant AM subpopulation to undergo apoptosis following exposure to fibrogenic agents; 3) apoptosis of the suppressor AM subpopulation allows stimulatory AM to activate T helper cells that ultimately progresses to lung fibrosis. The specific aims of the proposal are to: 1) characterize the involvement of the class A type I/II scavenger receptor (SRA) and the caspase family of proteases in initiating and regulating the induction of AM apoptosis and fibrosis by silica and asbestos; 2) characterize the involvement of T helper cells in silica and asbestos-induced lung fibrosis; 3) characterize AM phenotypes and epitopes corresponding to the phenotype markers and confirm that silica and asbestos induce apoptosis of the suppressor AM phenotype. Aims 1 and 2 will be accomplished using SRA knockout mice, SRA antagonists and caspase inhibitors, as well as mice that are cytokine knockouts and transgenics. These studies will focus on determining the requirements of AM apoptosis to signaling T helper cell activation leading to lung fibrosis. Aim 3 will be accomplished by isolating and characterizing the phenotypes of different subpopulations of human AM and examining their functions and responses to silica and asbestos induced apoptosis. The proteins corresponding to the epitopes will be characterized and AM from fibrotic patients will be examined. The importance of the work relates to the large numbers of asbestos and silica exposed individuals, and to the continual exposure of the public to potentially fibrogenic particles in the urban environment. By improving understanding of these mechanisms, this work may allow development of improved therapies.